tbuckley/cabot-search huggingface dataset:
Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer
Authors: Sakti Chakrabarti, Leslie Bucheit, Jason Scott Starr, Racquel Innis-Shelton, Ardaman Shergill, Hiba Dada, Regina Resta, Stephanie Wagner, Naomi Fei, Pashtoon Murtaza Kasi
Journal: Journal for ImmunoTherapy of Cancer (2022)

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56–82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1–24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11–33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.
Emergency care in hospitals is as good at the weekend as on weekdays
Authors: Helen Saul, Deniz Gursul, Julian Bion
Journal: BMJ (2022)

The studyBion J, Aldridge C, Beet C, et al. Increasing specialist intensity at weekends to improve outcomes for patients undergoing emergency hospital admission: the HiSLAC two-phase mixed-methods study. HSDR 2021;9:13.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/hospital-emergency-care-is-as-good-at-the-weekend-as-on-weekdays/.
Diagnostic accuracy of rapid one-step PCR assays for detection of herpes simplex virus-1 and -2 in cerebrospinal fluid: a systematic review and meta-analysis
Authors: Esther Vaugon, Alexandra Mircescu, Chelsea Caya, Mandy Yao, Genevieve Gore, Nandini Dendukuri, Jesse Papenburg
Journal: Clinical Microbiology and Infection (2022)
Detection of cancer cells and tumor margins during colorectal cancer surgery by intraoperative flow cytometry
Authors: Vaia K. Georvasili, Georgios S. Markopoulos, Anna Batistatou, Michael Mitsis, Thomas Messinis, Georgios D. Lianos, George Alexiou, George Vartholomatos, Christina D. Bali
Journal: International Journal of Surgery (2022)
Functional Divergence of the<i>bag-of-marbles</i>Gene in the<i>Drosophila melanogaster</i>Species Group
Authors: Jaclyn E Bubnell, Cynthia K S Ulbing, Paula Fernandez Begne, Charles F Aquadro
Journal: Molecular Biology and Evolution (2022)

Abstract In Drosophila melanogaster, a key germline stem cell (GSC) differentiation factor, bag of marbles (bam) shows rapid bursts of amino acid fixations between sibling species D. melanogaster and Drosophila simulans, but not in the outgroup species Drosophila ananassae. Here, we test the null hypothesis that bam’s differentiation function is conserved between D. melanogaster and four additional Drosophila species in the melanogaster species group spanning approximately 30 million years of divergence. Surprisingly, we demonstrate that bam is not necessary for oogenesis or spermatogenesis in Drosophila teissieri nor is bam necessary for spermatogenesis in D. ananassae. Remarkably bam function may change on a relatively short time scale. We further report tests of neutral sequence evolution at bam in additional species of Drosophila and find a positive, but not perfect, correlation between evidence for positive selection at bam and its essential role in GSC regulation and fertility for both males and females. Further characterization of bam function in more divergent lineages will be necessary to distinguish between bam’s critical gametogenesis role being newly derived in D. melanogaster, D. simulans, Drosophila yakuba, and D. ananassae females or it being basal to the genus and subsequently lost in numerous lineages.
Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study
Authors: Xin You Tai, Michele Veldsman, Donald M Lyall, Thomas J Littlejohns, Kenneth M Langa, Masud Husain, Janice Ranson, David J Llewellyn
Journal: The Lancet Healthy Longevity (2022)

BackgroundIndividual cardiometabolic disorders and genetic factors are associated with an increased dementia risk; however, the relationship between dementia and cardiometabolic multimorbidity is unclear. We investigated whether cardiometabolic multimorbidity increases the risk of dementia, regardless of genetic risk, and examined for associated brain structural changes.MethodsWe examined health and genetic data from 203 038 UK Biobank participants of European ancestry, aged 60 years or older without dementia at baseline assessment (2006–10) and followed up until March 31, 2021, in England and Scotland and Feb 28, 2018, in Wales, as well as brain structural data in a nested imaging subsample of 12 236 participants. A cardiometabolic multimorbidity index comprising stroke, diabetes, and myocardial infarction (one point for each), and a polygenic risk score for dementia (with low, intermediate, and high risk groups) were calculated for each participant. The main outcome measures were incident all-cause dementia and brain structural metrics.FindingsThe dementia risk associated with high cardiometabolic multimorbidity was three times greater than that associated with high genetic risk (hazard ratio [HR] 5·55, 95% CI 3·39–9·08, p<0·0001, and 1·68, 1·53–1·84, p<0·0001, respectively). Participants with both a high genetic risk and a cardiometabolic multimorbidity index of two or greater had an increased risk of developing dementia (HR 5·74, 95% CI 4·26–7·74, p<0·0001), compared with those with a low genetic risk and no cardiometabolic conditions. Crucially, we found no interaction between cardiometabolic multimorbidity and polygenic risk (p=0·18). Cardiometabolic multimorbidity was independently associated with more extensive, widespread brain structural changes including lower hippocampal volume (F2, 12 110 = 10·70; p<0·0001) and total grey matter volume (F2, 12 236 = 55·65; p<0·0001).InterpretationCardiometabolic multimorbidity was independently associated with the risk of dementia and extensive brain imaging differences to a greater extent than was genetic risk. Targeting cardiometabolic multimorbidity might help to reduce the risk of dementia, regardless of genetic risk.FundingWellcome Trust, Alzheimer's Research UK, Alan Turing Institute/Engineering and Physical Sciences Research Council, the National Institute for Health Research Applied Research Collaboration South West Peninsula, National Health and Medical Research Council, JP Moulton Foundation, and National Institute on Aging/National Institutes of Health.
17P Correlation between human papillomavirus clearance and complete response among Mexican patients with locally advanced cervical cancer treated with chemoradiotherapy
Authors: M.F. Noriega Iriondo, J.F. Gonzalez Guerrero, J.L. Gonzalez Vela, D. Ruiz-Sánchez, M. Zamudio-Osuna, L.E. Martínez-De Villarreal, D. Hernandez Barajas, O. Vidal-Gutiérrez, C.E. Salazar-Mejía
Journal: Annals of Oncology (2022)
Baroreflex activation therapy with the <scp>Barostim</scp>™ device in patients with heart failure with reduced ejection fraction: a patient level meta‐analysis of randomized controlled trials
Authors: Andrew J.S. Coats, William T. Abraham, Michael R. Zile, Joann A. Lindenfeld, Fred A. Weaver, Marat Fudim, Johann Bauersachs, Sue Duval, Elizabeth Galle, Faiez Zannad
Journal: European Journal of Heart Failure (2022)

Heart failure with reduced ejection fraction (HFrEF) remains associated with high morbidity and mortality, poor quality of life (QoL) and significant exercise limitation. Sympatho-vagal imbalance has been shown to predict adverse prognosis and symptoms in HFrEF, yet it has not been specifically targeted by any guideline-recommended device therapy to date. Barostim™, which directly addresses this imbalance, is the first Food and Drug Administration approved neuromodulation technology for HFrEF. We aimed to analyse all randomized trial evidence to evaluate the effect of baroreflex activation therapy (BAT) on heart failure symptoms, QoL and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFrEF.An individual patient data (IPD) meta-analysis was performed on all eligible trials that randomized HFrEF patients to BAT + guideline-directed medical therapy (GDMT) or GDMT alone (open label). Endpoints included 6-month changes in 6-min hall walk (6MHW) distance, Minnesota Living With Heart Failure (MLWHF) QoL score, NT-proBNP, and New York Heart Association (NYHA) class in all patients and three subgroups. A total of 554 randomized patients were included. In all patients, BAT provided significant improvement in 6MHW distance of 49 m (95% confidence interval [CI] 33, 64), MLWHF QoL of -13 points (95% CI -17, -10), and 3.4 higher odds of improving at least one NYHA class (95% CI 2.3, 4.9) when comparing from baseline to 6 months. These improvements were similar, or better, in patients who had baseline NT-proBNP &lt;1600 pg/ml, regardless of the cardiac resynchronization therapy indication status.An IPD meta-analysis suggests that BAT improves exercise capacity, NYHA class, and QoL in HFrEF patients receiving GDMT. These clinically meaningful improvements were consistent across the range of patients studies. BAT was also associated with an improvement in NT-proBNP in subjects with a lower baseline NT-proBNP.
Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness
Authors: Vineesh Indira Chandran, Charlotte Wilhelmina Wernberg, Mette Munk Lauridsen, Maria Kløjgaard Skytthe, Sofie Marchsteiner Bendixen, Frederik Tibert Larsen, Camilla Dalby Hansen, Lea Ladegaard Grønkjær, Majken Storm Siersbæk, Tina Di Caterino, Sönke Detlefsen, Holger Jon Møller, Lars Grøntved, Kim Ravnskjaer, Søren Kragh Moestrup, Maja Sofie Thiele, Aleksander Krag, Jonas Heilskov Graversen
Journal: Hepatology (2022)

Background and Aims: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. Approach and Results: We collected cross‐sectional, clinical data including liver biopsies from a derivation ( n = 48) and a validation cohort ( n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84–0.99). In the validation cohort, plasma TREM2 level increased approximately two‐fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77–0.89; p &lt; 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning ( p &lt; 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule‐in and rule‐out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule‐out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule‐in cutoff (specificity 89%; sensitivity 54%). Conclusions: Plasma TREM2 is a plausible individual biomarker that can rule‐in or rule‐out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.
Automatic Grading Assessments for Knee MRI Cartilage Defects via Self-ensembling Semi-supervised Learning with Dual-Consistency
Authors: Jiayu Huo, Xi Ouyang, Liping Si, Kai Xuan, Sheng Wang, Weiwu Yao, Ying Liu, Jia Xu, Dahong Qian, Zhong Xue, Qian Wang, Dinggang Shen, Lichi Zhang
Journal: Medical Image Analysis (2022)
Time to Cure for Childhood and Young Adult Acute Lymphoblastic Leukemia Is Independent of Early Risk Factors: Long-Term Follow-Up of the UKALL2003 Trial
Authors: Anthony V. Moorman, Grace Antony, Rachel Wade, Ellie R. Butler, Amir Enshaei, Christine J. Harrison, John Moppett, Rachael Hough, Clare Rowntree, Jeremy Hancock, Nicholas Goulden, Sujith Samarasinghe, Ajay Vora
Journal: Journal of Clinical Oncology (2022)

PURPOSE The aim of the randomized trial, UKALL2003, was to adjust treatment intensity on the basis of minimal residual disease (MRD) stratification for children and young adults with acute lymphoblastic leukemia. We analyzed the 10-year randomized outcomes and the time for patients to be considered cured (ClinicalTrials.gov identifier: NCT00222612 ). METHODS A total of 3,113 patients were analyzed including 1,054 patients who underwent random assignment (521 MRD low-risk and 533 MRD high-risk patients). Time to cure was defined as the point at which the chance of relapse was &lt; 1%. The median follow-up time was 10.98 (interquartile range, 9.19-13.02) years, and survival rates are quoted at 10 years. RESULTS In the low-risk group, the event-free survival was 91.7% (95% CI, 87.4 to 94.6) with one course of delayed intensification versus 93.7% (95% CI, 89.9 to 96.1) with two delayed intensifications (adjusted hazard ratio, 0.73; 95% CI, 0.38 to 1.40; P = .3). In the high-risk group, the event-free survival was 82.1% (95% CI, 76.9 to 86.2) with standard therapy versus 87.1% (95% CI, 82.4 to 90.6) with augmented therapy (adjusted hazard ratio, 0.68; 95% CI, 0.44 to 1.06; P = .09). Cytogenetic high-risk patients treated on augmented therapy had a lower relapse risk (22.1%; 95% CI, 15.1 to 31.6) versus standard therapy (52.4%; 95% CI, 28.9 to 80.1; P = .016). The initial risk of relapse differed significantly by sex, age, MRD, and genetics, but the risk of relapse for all subgroups quickly coalesced at around 6 years after diagnosis. CONCLUSION Long-term outcomes of the UKALL2003 trial confirm that low-risk patients can safely de-escalate therapy, while intensified therapy benefits patients with high-risk cytogenetics. Regardless of prognosis, the time to cure is similar across risk groups. This will facilitate communication to patients and families who pose the question “When am I/is my child cured?”
19TiP SGNTUC-019 phase II basket study of tucatinib and trastuzumab in solid tumors with human epidermal growth factor receptor 2 alterations: Uterine and cervical cancer cohorts
Authors: D. O'Malley, F.J. Jin, J.D. Ramos, Q. Tan, B.J. Monk
Journal: Annals of Oncology (2022)
Local production of broadly cross‐reactive <scp>IgE</scp> against multiple fungal cell wall polysaccharides in patients with allergic fungal rhinosinusitis
Authors: Soichiro Haruna, Kazuya Takeda, Marwa Ali El‐Hussien, Yohei Maeda, Masaki Hayama, Takashi Shikina, Katsumi Doi, Hidenori Inohara, Hitoshi Kikutani, Shuhei Sakakibara
Journal: Allergy (2022)

Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature
Authors: Patrick Coit, Xiavan Roopnarinesingh, Lourdes Ortiz-Fernández, Kathleen McKinnon-Maksimowicz, Emily E Lewis, Joan T Merrill, W Joseph McCune, Jonathan D Wren, Amr H Sawalha
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Lupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional lupus-associated DNA methylation changes and determine the genetic contribution to epigenetic changes characteristic of lupus. Methods Genome-wide DNA methylation was assessed in naïve CD4 + T cells from 74 patients with lupus and 74 age-matched, sex-matched and race-matched healthy controls. We applied a trend deviation analysis approach, comparing methylation data in our cohort with over 16 500 samples. Methylation quantitative trait loci (meQTL) analysis was performed by integrating methylation profiles with genome-wide genotyping data. Results In addition to the previously reported epigenetic signature in interferon-regulated genes, we observed hypomethylation in the promoter region of the miR-17-92 cluster in patients with lupus. Members of this microRNA cluster play an important role in regulating T cell proliferation and differentiation. Expression of two microRNAs in this cluster, miR-19b1 and miR-18a, showed a significant positive correlation with lupus disease activity. Among miR-18a target genes, TNFAIP3 , which encodes a negative regulator of nuclear factor kappa B, was downregulated in lupus CD4 + T cells. MeQTL identified in lupus patients showed overlap with genetic risk loci for lupus, including CFB and IRF7 . The lupus risk allele in IRF7 (rs1131665) was associated with significant IRF7 hypomethylation. However, &lt;1% of differentially methylated CpG sites in patients with lupus were associated with an meQTL, suggesting minimal genetic contribution to lupus-associated epigenotypes. Conclusion The lupus defining epigenetic signature, characterised by robust hypomethylation of interferon-regulated genes, does not appear to be determined by genetic factors. Hypomethylation of the miR-17-92 cluster that plays an important role in T cell activation is a novel epigenetic locus for lupus.
Patient‐centered care: Key elements applicable to chronic liver disease
Authors: Manisha Verma, Mayur Brahmania, Brett E. Fortune, Sumeet K. Asrani, Michael Fuchs, Michael L. Volk
Journal: Hepatology (2022)

Chronic liver disease (CLD) is a progressive illness with high symptom burden and functional and cognitive impairment, often with comorbid mental and substance use disorders. These factors lead to significant deterioration in quality of life, with immense burden on patients, caregivers, and healthcare. The current healthcare system in the United States does not adequately meet the needs of patients with CLD or control costs given the episodic, reactive, and fee-for-service structure. There is also a need for clinical and financial accountability for CLD care. In this context, we describe the key elements required to shift the CLD care paradigm to a patient-centered and value-based system built upon the Porter model of value-based health care. The key elements include (1) organization into integrated practice units, (2) measuring and incorporating meaningful patient-reported outcomes, (3) enabling technology to allow innovation, (4) bundled care payments, (5) integrating palliative care within routine care, and (6) formalizing centers of excellence. These elements have been shown to improve outcomes, reduce costs, and improve overall patient experience for other chronic illnesses and should have similar benefits for CLD. Payers need to partner with providers and systems to build upon these elements and help align reimbursements with patients' values and outcomes. The national organizations such as the American Association for Study of Liver Diseases need to guide key stakeholders in standardizing these elements to optimize patient-centered care for CLD.
Cohort Study of Oligorecurrent Prostate Cancer Patients: Oncological Outcomes of Patients Treated with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen–radioguided Surgery
Authors: Sophie Knipper, Mehrdad Mehdi Irai, Ricarda Simon, Daniel Koehler, Isabel Rauscher, Matthias Eiber, Fijs W.B. van Leeuwen, Pim van Leeuwen, Hilda de Barros, Henk van der Poel, Lars Budäus, Thomas Steuber, Markus Graefen, Pierre Tennstedt, Matthias M. Heck, Thomas Horn, Tobias Maurer
Journal: European Urology (2022)
Intranasal antihistamine and corticosteroid to treat allergic rhinitis: A systematic review and meta‐analysis
Authors: Minji Kim, Gwanghui Ryu, Sung‐Yoon Kang, Mi‐Ae Kim, Song‐I Yang, Il Hwan Lee, Gil‐Soon Choi, Hyun‐Jung Kim, Sang Min Lee, Dong‐Kyu Kim, Jeong Hee Choi, Hyeon‐Jong Yang, Soo Whan Kim
Journal: Allergy (2022)

Fig S1 Fig S2 Fig S3 Fig S4 Fig S5 Fig S6 Fig S7 Fig S8 Table S1 Table S2 Table S3 Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Myeloid cell tropism enables MHC-E–restricted CD8 <sup>+</sup> T cell priming and vaccine efficacy by the RhCMV/SIV vaccine
Authors: Scott G. Hansen, Meaghan H. Hancock, Daniel Malouli, Emily E. Marshall, Colette M. Hughes, Kurt T. Randall, David Morrow, Julia C. Ford, Roxanne M. Gilbride, Andrea N. Selseth, Renee Espinosa Trethewy, Lindsey M. Bishop, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Lorna Silipino, Michael Nekorchuk, Kathleen Busman-Sahay, Jacob D. Estes, Michael K. Axthelm, Jeremy Smedley, Danica Shao, Paul T. Edlefsen, Jeffrey D. Lifson, Klaus Früh, Jay A. Nelson, Louis J. Picker
Journal: Science Immunology (2022)

The strain 68-1 rhesus cytomegalovirus (RhCMV)–based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8 + T cells that recognize epitopes presented by major histocompatibility complex (MHC)–II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II– and/or MHC-Ia–restricted CD8 + T cells do not protect against SIV, it remains unclear whether MHC-E–restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II–restricted component. Using host microRNA (miR)–mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope–targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142–mediated tropism restriction eliminated MHC-E epitope–targeted CD8 + T cell priming, yielding an exclusively MHC-II epitope–targeted response. Inhibition with the endothelial cell–selective miR-126 eliminated MHC-II epitope–targeted CD8 + T cell priming, yielding an exclusively MHC-E epitope–targeted response. Dual miR-142 + miR-126–mediated tropism restriction reverted CD8 + T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8 + T cell responses were generally similar, only the vectors programmed to elicit MHC-E–restricted CD8 + T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.